Smart Pills: Not Your Grandma’s Average Capsules
Adam Polak was 30 years old when he was diagnosed with Ulcertive Colitis, an inflammatory bowel disease (IBD).
He ignored all the signs of colitis since he was embarrassed but then caved in when the pain became unbearable. From abdominal pain to sudden bowel movements, the disease went from him having to go to the washroom 20 times a day, to him having to take a 13-month break off of his job as a flight attendant.
Eventually, he had to quit his job and he went to the doctor when he found out:
Oh my freaking God, I might have colon cancer.
He thinks it might not be so bad, until he goes to the doctor, is handed a pamphlet with the word “colitis” circled and is reading about how the IBD in his body has no cure.
Since there’s no cure, Adam was in clinical trials where every 2 weeks his stomach would be injected with drugs. It’s more painful than it sounds.
One year later he had to receive an endoscopy which is a highly invasive procedure where a lighted tube is inserted into the anus to examine the colon and rectum. Would have been a lot more painful if he wasn’t put on anaesthesia.
Living with an incurable disease is hard as it is, but making constant doctor visits to receive the proper medications while in pain and having numerous surgeries without being able to live a ‘normal’ life, it’s not easy.
Well, what if there was a way to solve this.
Finding the cure to this disease is difficult, but what if we could help improve the lifestyle of Adam and many others with disorders in different parts of the body.
Introducing smart pills.
Smart pills use nanotechnology to improve drug delivery to every part of the body, including the gastrointestinal (GI) tract.
P.S. If you would like to see more about smart pills, check out my Youtube video (linked here and at the bottom of this article 👇 )
Nanotechnology + Medicine = Nanomedicine
Nanotechnology — a pretty long word for a technology so small!
Nanotech is essentially controlling matter at the nanoscale. It allows us to control individual molecules and atoms which leads to incredible applications. These structures, atoms and molecules and practically anything at the nanoscale has novel properties because of their size.
So, think of science as a game.
In this game, a nanometer itself is one-billionth the size of a metre!
To bring this to perspective, a piece of paper is about 100 000 nm thick. A human hair can range from 50 000–100 000 nm thick. And if every single person on our planet was the size of a nanometer, we would all be able to fit into a car. A hotwheels car.
Let’s go deeper into these novel properties.
When elements and different chemicals are brought to the nanoscale, their properties change. For example, copper becomes transparent on the nanoscale and gold, which is normally unreactive, becomes highly reactive on the nanoscale.
So, the game of science basically has different rules on the nanoscale.
However, these ‘different rules’ can be used to our advantage, especially in medicine.
From creating nanobots (mini surgeons in your body) to screening for cancer, nanomedicine is the intersection of nanotech and medicine.
If you’re interested in how nanotech can be used within cancer, check out my article linked below:
Over these past few weeks, I dived deep into smart pills and using nanoparticles for drug delivery!
Pills of the Future
Alright, so nanotechnology is basically everything at a really small scale and it can be used in drug delivery within our bodies. But what exactly are these “Smart Pills” that keep being brought up?
Well, smart pills are these nano-level electronic devices that are shaped and designed as typical pharmaceutical pills. Now, they make look like your average Advil tablet but they can perform far more advanced functions. Smart pills can perform tasks ranging from producing images to enhanced targeted drug delivery.
The problem with current pills or injections is that the drug released isn’t targeted. Instead, the drug is released across the bloodstream, to multiple organs or the drug never actually reaches the intended site. Conventional drug delivery systems (DDS) cause numerous side effects because of nonspecific biodistribution and uncontrollable drug release.
However smart DDS (ex. Smart pills), reduce the dosage frequency and maintain the drug’s concentration for a long time. Nanoparticle based DDS allow for selective accumulation of the drug and controlled release.
There have been numerous different types of smart pills which have come out over the past two decades like the Pill Cam. The pill cam was almost like an ingestible camera to produce images of sensitive areas in the body. The pill cam was FDA approved and reduced the use of invasive procedures like endoscopies!
This is just one smart pill that could and will make Adam’s life easier.
There were even dose-tracking pills with built-in sensors which would track the medications within a patient’s body both internally and through the skin by a patch worn by the patient. The patch and the pill would then connect to an app on the patient’s cellphone to help track the dosage released, the time of release and would share this information with the doctor.
These are just two examples of the hundreds of doors nanotech has opened with the use of these smart pills.
However, there are two particular smart pills which have incredible uses and they are the Atmo Gas Capsule and MITs Smart Sensor Capsules.
In short, the MIT smart sensor capsules can unfold into a y-shape and launch into the stomach and stay there for about a month. These capsules contain sensors which track vital changes within the stomach (varies from disease to disease) for diagnosis and treatment. They also have preloaded compartments filled with medications and can be customised to release those drugs.
The Atmo Gas Capsules contain a permeable membrane (allows gases and drugs to enter and exit the membrane/capsules). The sensors within these capsules detect levels of oxygen, hydrogen and carbon-dioxide. The oxygen gas levels allow the doctors to pinpoint the capsule’s location.
Although those were VERY brief summaries of these smart pills, here’s a little more in depth breakdown on how the pills actually function.
MIT Smart Sensor Capsules
These smart pills prevent the need for injecting drugs into the stomach. After ingested orally, the pill unfolds itself into a Y-shape before launching itself onto any organ. These capsules also have various compartments used to preload medicines to be released onto targeted areas in the body!
These capsules are coated with antibodies (used to detect foriegn bacteria) which act as our keys to unlocking receptors found on the surface of the cells which line our intestines. This allows particles to break through the intestinal walls and actually enter the bloodstream.
As mentioned before, these capsules eliminate the need of injections. This is because the pills carry drugs, but normal injections don’t consider the fact that tumours and other diseased tissues are surrounded by leaky blood vessels. Therefore, patients receive injections, the drugs seep through the blood vessels and release at the tumour sight causing the drugs to enter the bloodstream as well. But, this is not the case with the smart pills.
Think of it like the game of science has a ‘go to jail’ card. You’re trying to make it to the end of the game but this barrier won’t let you continue.
Now to get rid of this barrier, you can’t just go through the jail cell bars because they’re too close together, so instead, you have to pivot.
Either you skip a turn or get a ‘get out of jail free’ card or, since it’s the game of science, there’s ‘different rules’. So, I guess you can also become really really small, almost the size of a nanoparticle and try getting through these cell bars.
This concept remains the same when looking at drug delivery within the body.
Since the smart sensor capsules are taken orally, they need to get through the intestinal lining to reach the stomach. However, this lining is made of epithelial cells which tightly join together to form impenetrable barriers and tight junctions, this is the jail cell bars.
These impenetrable barriers make it impossible for drugs and other substances to get through these layers. The tight junctions are essentially closely associated areas of cell membranes which join together to then form the impenetrable barrier. These tight junctions hold cells together and reduce the ability of larger molecules to pass between cells.
Now the challenge here is to make the nanoparticle sized pill to physically get through that wall of cells.
When cells want to form a barrier, they make these attachments from cell to cell, almost like a brick wall where the bricks are the cells and the mortar are the attachments) and nothing can penetrate that wall.
Now, you may be thinking, why don’t you just temporarily break that wall.
Well, let’s go back to our analogy. If we were to break the jail cell bars, our other inmates would be freed as well. And since we want to win the game, that wouldn’t be the ideal choice.
Just like the jail cell, if researchers tried to temporarily disrupt the tight junctions, the drugs would go through the walls, but so would other harmful bacteria.
And so, the researchers discovered, instead of disrupting the wall, they need to build nanoparticles which could selectively break through that barrier.
To do so, they looked at babies. Yup, you read that correctly. The researchers dove deep into how babies absorb antibodies through their mother’s breast milk since it helped boost their own immune defences.
They realised that the antibodies grab onto a cell surface receptor. Cell surface receptors are essentially receptors that are embedded onto the plasma membranes of cells and they’re proteins which allow for communication between the cell and its environment.
Think of it like this. You’ve shrunk yourself down to the size of a nanoparticle and can almost escape and make it through the jail cell bars, but you need a little assistance.
You see a nearby pole and decide to throw a rope so that one end will wrap around the pole. Then, you wrap the other end around yourself.
The rope is pulled and along with the rope being pulled out of the cell bars, you get pulled out as well.
In the case of the smart pill, antibodies grab onto the receptor called FcRN (like the rope wrapped around the pole) which allows them access through the epithelial cells (in the lining) into the adjacent blood vessels. The researchers coated the nanoparticles with Fc proteins which is the corresponding part of the antibody that binds to the FcRN receptor found in intestinal cells (like you wrapping the other side of the rope to your body).
After the pills are ingested, the Fc proteins grab onto the FcRN receptors in the intestinal lining and gain entry through the wall and they bring the nanoparticle with them since the particle is coated with the protein (like you and the rope escaping the jail cell bars).
Therefore, any drug or molecule that has difficulty crossing the barrier would be loaded within the nanoparticle and would be trafficked across.
Atmo Gas Capsules
Gastrointestinal (GI → any diseases in the intestinal tract — from mouth to anus) disorders affect 1 in 5 people in their lifetime, just like Adam, but a third of these cases remain unsolved. Well, introducing the new solution to solving all GI disorders: Atmo Gas Capsules.
When ingested, the atmo gas capsules examine the gases within the human gut to report any disorders. The sensors within these capsules detect the O2 and CO2 levels within the body, alongside the presence of any harmful substances.
The applications of this capsule range from diagnosing GI disorders to tracking food sensitivities!
The current methods for diagnosing GI diseases are highly invasive with many limitations.
Instead, the atmo gas capsules have a better and less invasive solution.
This capsule has a long polymer shell (polymer = anything made of a large number of smaller molecules to form larger molecules) with the following sensors all built using nanotech: gas sensors, temperature sensors, microcontroller, radio frequency transmitters and silver-oxide batteries.
The gas sensors are sealed within a nanomatrix and surrounded by a semipermeable membrane. This membrane allows gases in but keeps stomach acids and digestive juices outside of the capsule.
The capsule itself uses sensors to measure different gases by adjusting their heat elements. The oxygen gas concentrations are used to track the capsule’s progress through the gastrointestinal (GI) tract.
All the data collected is then transmitted to a small receiver which in turn, sends data (via Bluetooth) to the patients cell phone which can later be shown to the doctor.
The amazing thing about the atmo gas capsule is that it measures concentrations every 6 minutes!
Nano capsules
Smart pills combine nanotech-based sensors and nanoparticles to form a complex pharmaceutical pill. However, the nanoparticle aspect of these smart pills allow them to encapsulate, carry and deliver drugs across the body.
The Basics
Drug-filled nanocapsules are covered with antibodies and cell surface receptors (which bind onto disease cells) and they release their medications with controlled release and target specific delivery of drugs. The size of these nanocapsules range from 5–1000 nm but are normally 100–500 nm.
The drugs are inside the core cavity of the nanocapsules which protects them from any rapid degradation as they have an aqueous and oily core surrounded by a thin polymer membrane. The cavity encloses all active substances in the form of a liquid or solid.
Both nanocapsules (NCs) and nanospheres (NSs — link NS part of article) are prepared with a biodegradable polymer called PLA. This polymer acts as the membrane of the nanoparticle (NP) used to wrap hydrophilic (can dissolve and mix with water) or hydrophobic (repels water) drugs.
The NCs allow for incremental drug release and are created layer by layer.
This is when positively and negatively charged polymers add. Then, layer by layer, they self-assemble and form an ultrathin polymer film. In this film, each new layer is of the opposite charge of the last layer. Each film has approximately 4–20 layers and are about 8–50 nm thick.
I’ll go deeper into NCs later on in this article but they’ll be mentioned as polymeric nanoparticles.
Nanospheres
Nanospheres are like matrix systems where the drug is dissolved and then entrapped/encapsulated into a nanomatrix.
Since the smallest capillaries in the body range from 5–6 µm in diameter, the size of the particle has to be much smaller, which is why we resort to nanometers.
Polymeric Nanoparticles
Nanospheres, nanocapsules and lipid nanocapsules are just three examples of polymeric nanoparticles, however, this large umbrella has numerous subsets and general information which is vital to understand before diving deeper.
Firstly, polymeric NPs can be synthesised in multiple different ways, from emulsification to nanoprecipitation.
Generally, the therapeutics are encapsulated within the NP core and are entrapped in a polymer matrix/shell. These NPs enable the delivery of various payloads (hydrophobic, hydrophilic, cargos — anything carried by a protein). The properties of polymeric NPs can also be changed depending on the drug being delivered or a patient’s medical history. These properties include: stability, composition, responsivity, surface charge and the release/loading of the drug can also be precisely controlled.
Polymeric NPs have properties that can be engineered and fine-tuned for selective drug delivery and imaging agents. The negatives to these NPs however, are that they absorb proteins and immune complexes as they circulate and they also have limited permeation of their layers and tissues.
Polymeric NPs are the best nanoparticles for drug delivery. This is because, they’re biodegradable, water soluble, biocompatible and they remain stable during storage. Their surfaces can also easily be modified for additional targeting.
NP surfaces are wrapped with certain chemicals and can detect and target disease cells, tissues and tumours. For example, this smart DDS can actively be targeted using specific ligands (molecules that bind to another molecule) and with targeting moieties (attached to carrier molecules and surfaces of NPs).
Nanocapsules are the most common form of polymeric NPs and their core cavities are surrounded by polymeric shells. Nanocapsules can be further divided into polymersomes, micelles and dendrimers (we’ll be focusing on dendrimers).
Polymersomes are artificial vesicles (aka. fluid filled sacs) with membranes. They’re locally responsive and have incredible stability.
Polymeric Micelles
Polymeric micelles are very responsive and when in water, they self-assemble to form NS with a hydrophilic core and hydrophobic coating which protects the drug and improves circulation times.
The incredible thing with polymeric micelles is that they can load numerous drugs like small molecule proteins.
They’re also currently in clinical trials for cancer treatment!
Dendrimers/Dendritic Nanoparticles
Dendrimers are hyperbranched polymers with 3D shapes for the mass, sizes, shapes and surface chemicals to remain highly controlled. There are numerous active functional groups on the surface of these dendrimers which allow for the conjugation of biomolecules (where one bacterium transfers genetic information/material onto another bacterium). Dendrimers are also very unique since they can hold many different cargos, mainly ones for nucleic acids and small molecules.
Dendrimers and dendritic NPs have many biomedical applications as they have a controlled size, a near monodisperse structure (particles identical in shape and size) and their surface of varying terminal functional groups. However, some limitations of these NPs would be that they have rapid systemic elimination, inefficient tumour targeting and poor hydrophobic drug loading.
To overcome these barriers, we can engineer to our structural liking and alongside changing their hybridization with other nanocarriers.
Some examples of surface modifications include 2-faced dendrimers, integrating linear polymers and hybridization with other nanocarriers (mixing atomic orbitals to form new hybrid orbitals).
But before we get into engineering the dendritic polymers, understanding the architecture of the dendrimers and how they’re formed are vital for understanding how we can alter them.
Dendrimer Synthesis
Dendrimers are typically grown radially in a tightly controlled manner with sequential activation and condensation reactions. Each “next step” in the process of the reactions and forming the dendrimers are called generations (G).
There are two main methods of forming dendrimer: divergent and convergent.
Divergent synthesis is when the dendrimers are grown radially from a multifunctional core. Divergent formation allows for the surface to be easily modified during the last step allowing for an increased number of specific surface functionalities.
However, this method normally leads to more steps meaning there are more branching defects in the final products, mainly at higher generations.
Convergent synthesis on the other hand is when dendrons are individually synthesised to form the multifunctional core which in turn, forms dendrimers. This second method typically produces a lower number of generations and they have well-defined structures.
However, convergent synthesis causes a problem with space. This is because, as the size increases, space hindrance between the large dendrons causes a block formation of fully spherical dendrimers.
Dendrimers as a whole can also have a lot of structural defects if not produced correctly. For example, buying these nanoparticles from a store might contain dendrimers with 93 arms each but theoretically, each should have 128 arms.
However, these structures have very interesting architectural design allowing for various applications.
At each new generation, the number of surface functional groups increases. For example,
G2 = 16
G3 = 32
G7 = 512
The sizes of these dendrimers range from 10–90 nm and they have a high surface group to volume ratio. They have a highly flexible structure and smaller generations can adopt spherical structures.
Higher G dendrimers (G4+) have greater loading capacities since they have a densely packed surface compared to smaller G dendrimers. However, higher G dendrimers also have drug retention (absorb the drug while holding) which can cause an uncontrolled burst release of the encapsulated molecule. To prevent this however, covalent conjugation between molecules and dendrimers is necessary.
Eliminating Drawbacks
Let’s go back to the drawbacks now.
We can tackle these drawbacks in four different ways so lets go over all of them.
1. Chemical modifications
First off, we’ve got chemical modifications.
We can chemically modify the surface of the dendrimers in various ways, one of which being charge types. Charge types can range from imaging agents, therapeutic drugs to targeting ligands; however, these charge types are normally specific to the dendrimer and the case it’s tackling.
For example, a test was done to change the skin permeation of G2 PAMAM dendrimers. Researchers engineered the surface functionalities.
They decided to neutralise the surface which allowed for far better permeation through the outermost layer of the skin.
2. Janus/2-Faced Dendrimers
Janus dendrimers are known to have two opposing faces.
This is when dendrons with different compositions are linked together. The unique factor about these dendrimers is the fact that each face can be produced to have distinct surface functional groups allowing for precision of very complex cases.
3. LDBCs
Linear-dendritic block copolymers, also known as LDBCs, are normal dendritic polymers with additional linear polymers added onto them.
LDBCs are typically 9–18 nm in diameter but have numerous unique traits:
LDBCs can carry drug molecules and they even allow for amphiphilic dendritic polymers to self-assemble into larger micellar structures in aqueous solutions. These newly formed structures have a dense coating of a hydrophilic polymer known as PEG and can load hydrophobic drugs in their cores.
These dendrimers allow for targeted drug delivery as they facilitate multivalent binding. This is when the polymers can simultaneously bind multiple ligands and their receptors in highly localised areas.
LDBCs also construct stimuli-responsive NPs for targeted drug delivery. This is due to the well-defined nature of the dendron block as it allows for fine-tuning of the material properties in a controlled way.
For example, a study was done where pH-responsive LDBC-based micelles were tested for targeted drug delivery to a tumour. These NPs could encapsulate DOX (a medication) and selectively release it in acidic environments!
My simulation → Modelling dendritic polymers (PAMAM G1 and G2)
Dendrimers have a very complicated structure due to their functional groups and branches; however, look deeper into their chemical structures!
There currently is not the most diverse softwares to physically model these dendrimers, so I had to adapt.
I decided to use the software “Materials Square” to learn more about the chemical structure of the dendrimers. I decided to focus on PAMAM G1 and G2 dendrimers and started with drawing the molecules and ended up learning a lot about their structures.
I began with drawing the line diagrams of the PAMAM G1 dendrimer and right off the bat I noticed some characteristics:
- Cannot be identified as cis nor trans because all branches are identical
- Has 22 carbon atoms and it’s important to remember this number when comparing solubility.
- Has aldehyde functional groups
Then I considered the changes that could be added to this dendrimer:
- Add more functional groups — there’s a lot of space to do so — to specialise for a particular issue ex. Increasing skin permeation
- Can easily make this a Janus structure → replicate this structure, connect the two structures on the nitrogen cores and then change the functional groups. This would also cause this structure to be thought of as a G2 PAMAM dendrimer.
I took this same dendrimer line diagram and modelled it as a molecule:
It’s very easy to add a hydrophilic coating to this molecule to be able to carry hydrophobic drugs.
After briefly observing the G1 PAMAM polymer dendrimer, I moved on to the G2 PAMAM dendrimer. This structure is much more complicated as there’s an increasing number of functional groups with well over 4 branches.
Due to this structure being very complicated, the software was unable to model the entire structure into a molecule. Instead, I drew the line diagrams of ¼ of the structure, ½ of the structure and the full structure and then only modelled the ¼ structure and ½ structure.
¼ structure observations:
- When compared to the G1 dendrimer, this quarter of the dendrimer is much more complicated than the entire G1 structure.
- Total of 8 branches in this quarter of the structure.
- All branches are again identical — cannot identify cis or trans bonds
Molecular structure:
- All of the red atoms represent the aldehyde functional groups and when compared to G1, G2 has many more.
- The solubility of this dendrimer is also 0.5x greater than the G1.
Then, I added more and modelled the entire G2 dendrimers line diagram.
In this diagram, there are 32 branches where each and every single one of them are identical. The core of this dendrimer is of nitrogen and in a nanocapsule or nanosphere, the core would form into a circle and would actually carry the drug. While the branches would allow the capsule to move through the body with ease.
A hydrophobic coating of the drug would allow for hydrophilic drugs to be carried across the body which would revolutionise medicine!
Here’s a few more pictures of the simulation:
To hear more about my simulation and research, check out my youtube video linked below!
Smart pills and nanoparticles are small particles for big problems.
Nanoparticles have revolutionised the game of science, but with more clinical trials and more research, these small particles will be the next big thing in medicine.
They are: the pills of the future.
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